1. Field of the Invention
The invention relates to the use of immunomer compounds and immunostimulatory oligonucleotides as therapeutic agents.
2. Summary of the Related Art
Recently, several researchers have demonstrated the validity of the use of oligonucleotides as immunostimulatory agents in immunotherapy applications. The observation that phosphodiester and phosphorothioate oligonucleotides can induce immune stimulation has created interest in developing these compounds as a therapeutic tool. These efforts have focused on phosphorothioate oligonucleotides containing the natural dinucleotide CpG. Kuramoto et al., Jpn. J. Cancer Res. 83:1128-1131 (1992) teaches that phosphodiester oligonucleotides containing a palindrome that includes a CpG dinucleotide can induce interferon-alpha and gamma synthesis and enhance natural killer activity. Krieg et al., Nature 371:546-549 (1995) discloses that phosphorothioate CpG-containing oligonucleotides are immunostimulatory. Liang et al., J. Clin. Invest. 98:1119-1129 (1996) discloses that such oligonucleotides activate human B cells. Moldoveanu et al., Vaccine 16:1216-124 (1998) teaches that CpG-containing phosphorothioate oligonucleotides enhance immune response against influenza virus. McCluskie and Davis, J. Immunol. 161:4463-4466 (1998) teaches that CpG-containing oligonucleotides act as potent adjuvants, enhancing immune response against hepatitis B surface antigen.
Other modifications of CpG-containing phosphorothioate oligonucleotides can also affect their ability to act as modulators of immune response. See, e.g., Zhao et al., Biochem. Pharmacol. (1996) 51:173-182; Zhao et al., Biochem Pharmacol. (1996) 52:1537-1544; Zhao et al., Antisense Nucleic Acid Drug Dev. (1997) 7:495-502; Zhao et al., Bioorg. Med Chem. Lett. (1999) 9:3453-3458; Zhao et al., Bioorg. Med Chem. Lett. (2000) 10:1051-1054; Yu et al., Bioorg. Med. Chem. Lett. (2000) 10:2585-2588; Yu et al., Bioorg. Med. Chem. Lett. (2001) 11:2263-2267; and Kandimalla et al., Bioorg. Med Chem. (2001) 9:807-813. U.S. Pat. No. 6,426,334 shows the promise of these compounds as anti-cancer agents.
Another means by which an immune response may be modulated is through the therapeutic use of cytokines. Cytokines are soluble molecules that cells of the immune system produce to control reactions between other cells. Thus, cytokines are regulators of humoral and cellular immunity. An understanding of how T cells mediate the immune response is critical in order to modulate the response. CD4+ T helper (Th) cells differentiate along either the Th1 or Th2 pathway. The Th1 pathway is important for the generation of cell-mediated immunity and is characterized by the production of, for example, γ-interferon and interleukin-2 (IL-2). The Th2 response is important for the generation of humoral immunity and is characterized by the production of, for example, IL-4 and IL-5. The Th1 response is known to be critical for immune system defense against infections, e.g., viral infections, and immune system surveillance of the body for the removal of neoplastic cells.
Krieg, A., M. et al. (U.S. Pat. No. 6,429,199) and Krieg, A., M. et al. (U.S. Pat. No. 6,218,371) purport to teach the co-administration of immunostimulatory CpG oligonucleotides and cytokines, particularly GM-CSF. Decker et al. (Experimental Hematology 28:558-565. (2000)), demonstrate that the co-administration of IL-2 with CpG oligonucleotides increases TNF-α and IL-6 production in B-chronic lymphocytic (B-CLL) cells but not in normal B-cells.
These reports make clear that there remains a need to be able to further optimize the therapeutic effectiveness of immunostimulatory oligonucleotides for the treatment of disease and enhance the anticancer activity of immunostimulatory oligonucleotides.